Funded Studies
Objective/Rationale:
Abnormal accumulation of alpha-synuclein in the brain is associated with toxicity and disease progression in Parkinson’s and other neurodegenerative diseases. NPT001 has been shown to reduce aggregated alpha-synuclein in biochemical and cellular studies. This project will investigate multiple dose levels of NPT001 on disaggregation and clearance of alpha-synuclein deposits in transgenic pre-clinical models that accumulate alpha-synuclein in the brain. The goal of this project is to obtain preclinical efficacy data in a relevant pre-clinical model of disease to support further development of NPT001 for the treatment of Parkinson’s disease.
Project Description:
NPT001, a highly novel therapeutic candidate with potential disease-modifying activity, disrupts and clears a variety of amyloid aggregates from the brain. In addition to reducing amyloid-beta and tau aggregates, NPT001 has been shown to reduce alpha-synuclein fibrils in biochemical and cellular assays, and in one small in vivo study. NPT001 is being developed for Alzheimer’s disease and will enter toxicology studies later this year. Additional preclinical efficacy data are needed to support NPT001 development for Parkinson’s disease.
This project will investigate the efficacy and dose-dependency of NPT001 in aged, alpha-synuclein over-expressing pre-clinical models in collaboration with Dr. Eliezer Masliah at The University of California, San Diego. Following two weeks of chronic NPT001 administration, functional improvement and neuropathology will be assessed. Pending positive results, these data will support additional studies of NPT001 in Parkinson’s disease models.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
NPT001 represents a highly novel and multi-targeted approach to the treatment of neurodegenerative disease. Efficacy data in pre-clinical models would support the continued development of NPT001 for Parkinson’s disease.
Anticipated Outcome:
Based upon our preliminary data for reducing alpha-synuclein and other amyloid fibers, we anticipate that NPT001 will be effective in clearing alpha-synuclein deposits from the brains of transgenic pre-clinical models. It is expected that we will identify minimally and maximally effective doses that will support additional research in relevant models of PD.
Final Outcome
NPT001 has been shown to disrupt and clear a variety of amyloid aggregates in the brain. In addition to reducing beta amyloid and tau aggregates (hallmarks of Alzheimer’s disease) in pre-clinical models, preliminary studies indicated that NPT001 disrupts alpha-synuclein fibrils which are thought to play a role in PD. This project investigated the effects of multiple dose levels of NPT001 on neuropathology and motor performance in aged transgenic pre-clinical models expressing human alpha-synuclein.
NPT001 treatment produced significant reductions in neuropathology along with improved motor performance in a PD preclinical model. The study was conducted in collaboration with Dr. Eliezer Masliah at the University of California San Diego (UCSD) and demonstrated that NPT001, after a single treatment, significantly reduced alpha-synuclein deposits and increased tyrosine hydroxylase (TH) in the brain. The high dose of NPT001 restored TH to the level of normal, wildtype pre-clinical models. TH is a critical brain enzyme that is involved in dopamine synthesis and is deficient in PD. Deficits in dopamine production are responsible for many of the behavioral dysfunctions in PD. To this end, NPT001 treatment significantly improved motor performance at the highest dose used in the study. NPT001 was well-tolerated and produced no observable adverse effects.